EP3125902A2 - Use of negative modulators of gaba receptors containing alpha5 subunits as fast acting antidepressants - Google Patents
Use of negative modulators of gaba receptors containing alpha5 subunits as fast acting antidepressantsInfo
- Publication number
- EP3125902A2 EP3125902A2 EP15774070.5A EP15774070A EP3125902A2 EP 3125902 A2 EP3125902 A2 EP 3125902A2 EP 15774070 A EP15774070 A EP 15774070A EP 3125902 A2 EP3125902 A2 EP 3125902A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- gaba
- disorder
- depression
- receptor
- rats
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Definitions
- Embodiments of the disclosure are related at least to the fields of cell biology, molecular biology, biochemistry, neurology, psychiatry, pharmacology, psychology, and medicine.
- the disclosure relates to methods for treating or ameliorating depression and/or suicidality in a subject by administering one or more modulators of the GABA A receptor that can produce a rapid antidepressant action.
- SSRIs serotonin reuptake inhibitors
- the GABA A receptor is an ionotropic receptor and ligand gated ion channel. Its endogenous ligand is gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system.
- GABA gamma-aminobutyric acid
- the primary activation site of the GABA A receptor is the binding site for GABA and several drugs, such as muscimol, gaboxadol, and bicuculline. A second binding site is the so-called "benzodiazepine receptor" site. Drugs binding at this site can promote or impair the ability of GABA to activate the GABA A receptor.
- GABA A receptors occur in all organisms with a central nervous system. Because of their wide distribution within the nervous system of mammals, they play a role in virtually all brain functions.
- Ketamine a recognized antagonist of the NMDA-type glutamate receptor, has demonstrated fast-acting antidepressant properties.
- ketamine is recognized to have potent psychotomimetic effects and the mechanism of action of ketamine remains uncertain.
- Embodiments of the disclosure concern methods and compositions for the treatment of one or more medical conditions.
- the one or more medical conditions includes depression and similar conditions.
- the condition may be of any kind, but in specific embodiments the condition being treated is major depression and/or suicidality.
- treatment of the medical condition occurs at a more rapid rate than currently known treatments and has fewer deleterious side effects.
- the medical condition is a depression-related disorder; an anxiety-related disorder; an attention-related disorder; a psychosis-related disorder; an eating disorder; a personality disorder; cognitive impairment, including that follows traumatic brain injury (TBI) or that is non- TBI cognitive impairment; neuropathic pain; chronic muscle or bone pain; diabetic complications resulting in nerve injury; generalized attack of muscular weakness; recurring sleep episodes during the day; migraine; addiction; or a combination thereof.
- TBI traumatic brain injury
- neuropathic pain chronic muscle or bone pain
- diabetic complications resulting in nerve injury generalized attack of muscular weakness
- recurring sleep episodes during the day migraine
- addiction or a combination thereof.
- Embodiments of the present disclosure relate to a method for treating or ameliorating depression and/or suicidality in a human subject comprising administering to the subject a therapeutically effective amount of a modulator of a GABA A receptor.
- a modulator of a GABA A receptor that ameliorates a medical condition as described herein
- the modulator is a negative modulator of the receptor.
- the modulator is a negative allosteric modulator of GABA A receptors containing an alpha5 subunit.
- Specific embodiments of the disclosure concern the use of negative allosteric modulators of alpha5 subunit-containing GABA receptors as fast-acting antidepressants to address depression and/or reduce suicidality.
- fast-acting as used herein is defined as the onset of therapeutic effects being within hours to days compared to current therapies that take days to weeks to months.
- any and all drugs that are negative allosteric modulators of alpha5 subunit-containing GABA receptors will produce a rapid antidepressant action and will produce a rapid decrease in depression and/or suicidality in patients suffering from major depression or in patients suffering from depression that are not suicidal.
- alpha5-containing GABA receptors are narrowly expressed in the hippocampus and cortex, and because in at least some embodiments the substances are weak inverse agonists, in certain embodiments they have a significantly greater therapeutic potential than current treatments.
- the present disclosure relates to a method for treating or ameliorating depression and/or suicidality in a human subject comprising administering to the subject a therapeutically effective amount of a negative allosteric modulator of the GABA A receptor, and in some embodiments the modulator is administered orally, intradermally, intramuscularly, intraperitonealy, intravenously, via insufflation, or in a dermal patch.
- the present disclosure relates to a method for treating or ameliorating depression and/or suicidality in a human subject comprising administering to the subject a therapeutically effective amount of a negative allosteric modulator of the alpha5 subunit of the GABA A receptor and in some embodiments the modulator is administered orally intradermally, intramuscularly, intraperitonealy, intravenously, via insufflation, or in a dermal patch.
- the present disclosure relates to a method for treating or ameliorating depression and/or suicidality in a human subject comprising administering to the subject a therapeutically effective amount of L655,708 or a derivative or analog thereof and wherein L655,708 is (but not limited to) administered orally, intradermally, intramuscularly, intraperitoneally, intravenously, via insufflation, or in a dermal patch, in specific embodiments.
- the present disclosure relates to a method for treating or ameliorating depression and/or suicidality in a human subject comprising administering to the subject a therapeutically effective amount of MRK-016 or a derivative or analog thereof and wherein MRK-016 is (but not limited to) administered orally, intradermally, intramuscularly, intraperitoneally, intravenously, via insufflation, or in a dermal patch, in specific embodiments.
- the present disclosure relates to a method for treating or ameliorating depression and/or suicidality in a human subject comprising administering to the subject a therapeutically effective amount of CP-457,920 or a derivative or analog thereof and wherein CP-457,920 is (but not limited to) administered orally, intradermally, intramuscularly, intraperitoneally, intravenously, via insufflation, or in a dermal patch, in specific embodiments.
- the present disclosure relates to a method for treating or ameliorating depression and/or suicidality in a human subject comprising administering to the subject a therapeutically effective amount of RG-1662 or a derivative or analog thereof and wherein RG-1662 is (but not limited to) administered orally, intradermally, intramuscularly, intraperitoneally, intravenously, via insufflation, or in a dermal patch, in specific embodiments.
- the present disclosure relates to a method for treating or ameliorating depression and/or suicidality in a human subject comprising administering to the subject a therapeutically effective dose of a negative allosteric modulator of the alpha5 subunit- containing GABA A receptor either alone or in combination with an another antidepressant drug including, for example, one or more selected from the group consisting of monoamine oxidase inhibitors (MAOis), selective serotonin reuptake inhibitors(SSRis), serotonin-norepinephrine reuptake inhibitors (SNRis), norepinephrine reuptake inhibitors (NRIs), triple reuptake inhibitors, modulators of CNS acetylcholine function, stimulants, anti-glucocorticoids, antagonists of NMDA-type glutamate receptors, tricylic antidepressants (TCAs), and a combination thereof.
- MAOis monoamine oxidase inhibitors
- SSRis selective serotonin
- the present disclosure relates to a method for treating or ameliorating depression and/or suicidality in a human subject comprising administering to the subject a therapeutically effective dose of one or more of L655,708; MRK-016; CP-457,920; RG-1662; or a derivative or analog thereof, either alone or in combination with one or more other antidepressant drugs selected from the group consisting of monoamine oxidase inhibitors (MAOis), selective serotonin reuptake inhibitors(SSRis), serotonin-norepinephrine reuptake inhibitors (SNRis), norepinephrine reuptake inhibitors (NRIs), triple reuptake inhibitors, modulators of CNS acetylcholine function, stimulants, anti-glucocorticoids, antagonists of NMDA-type glutamate receptors, tricylic antidepressants (TCAs), and combinations thereof.
- MAOis monoamine oxidase inhibitors
- SSRis
- the present disclosure relates to a method for treating or ameliorating unipolar and bipolar forms of depression, suicidality, and other depressive symptoms of unipolar and bipolar depression, posttraumatic stress disorder, and/or postpartum depression in a human subject comprising administering to the subject a therapeutically effective amount of one or more negative modulators of a GABA A receptor, including an alpha5 subunit- containing GABA A receptor and, in some embodiments, the modulator is a partial inverse agonist of an alpha5-containing GABA A receptor.
- the present disclosure relates to a method for treating or ameliorating unipolar and bipolar forms of depression, suicidality, and other depressive symptoms of unipolar and bipolar depression, posttraumatic stress disorder, and/or postpartum depression in a human subject comprising administering to the subject a therapeutically effective dose of one or more negative modulators of a GABA A receptors, such as an inverse agonist of the alpha5 subunit-containing GABA A receptor, for example, either alone or in combination with one or more other antidepressant drugs selected from the group consisting of monoamine oxidase inhibitors (MAOis), selective serotonin reuptake inhibitors(SSRis), serotonin-norepinephrine reuptake inhibitors (SNRis), norepinephrine reuptake inhibitors (NRIs), triple reuptake inhibitors, modulators of CNS acetylcholine function, stimulants, anti-glucocorticoids, antagonists of NMDA-type
- MAOis mono
- the present disclosure relates to a method for boosting excitatory synapse function in multiple brain regions of a human subject comprising administering to the subject a therapeutically effective amount of a negative modulator of the alpha5 subunit-containing GABA A receptor.
- the present disclosure relates to a method for restoring sucrose preference in a rodent animal model with stress-induced anhedonia wherein the sucrose preference increases following administration of a therapeutically effective amount of a negative modulators of a GABA A receptors, such as a negative modulator of the alpha5 subunit- containing GABA A receptor, such as L-655,708; MRK-016; CP-457,920; RG-1662; a derivative or analog thereof; or a combination thereof.
- a negative modulators of a GABA A receptors such as a negative modulator of the alpha5 subunit- containing GABA A receptor, such as L-655,708; MRK-016; CP-457,920; RG-1662; a derivative or analog thereof; or a combination thereof.
- the present disclosure relates to a method for treating or ameliorating depression and/or suicidality in a human subject comprising administering to the subject a therapeutically effective amount of compound L-655, 708 (ethyl (13aS)-7 -methoxy-9- oxo-11, 12,13,13 a-terahydro-9H-imidazo[ 1 ,5-a]pyrrolo[2, 1-c] [ 1 ,4]benzodiazepine-l- carboxylate; MRK-016; CP-457,920; RG-1662; a derivative or analog thereof; or a combination thereof.
- the present disclosure relates to a method for treating or ameliorating depression and/or suicidality in a human subject comprising administering to the subject a therapeutically effective amount of compound L-655,708; MRK-016; CP-457,920; RG- 1662; a derivative or analog thereof; or a combination thereof.
- the present disclosure relates to a method for treating or ameliorating depression and/or suicidality in a human subject comprising administering to the subject a therapeutically effective amount of compound L-655,708; MRK-016; CP-457,920; RG- 1662; a derivative or analog thereof; or a combination thereof that is administered to the subject orally, intradermally, intramuscularly, intravenously, intraperitoneally, via insufflation, or in a dermal patch, in certain embodiments.
- the present disclosure relates to a method for treating or ameliorating depression and/or suicidality in a human subject comprising administering to the subject a therapeutically effective dose of a negative allosteric modulator of GABA A receptor, including one that comprises an alpha5 subunit, and in some cases is an inverse agonist of the alpha5 subunit-containing GABA A receptor, wherein the modulator is one or more benzodiazepine binding site inverse agonists or other binding sites that produce negative allosteric modulation of GABA A receptors containing alpha5 subunits.
- a negative allosteric modulator of GABA A receptor including one that comprises an alpha5 subunit, and in some cases is an inverse agonist of the alpha5 subunit-containing GABA A receptor, wherein the modulator is one or more benzodiazepine binding site inverse agonists or other binding sites that produce negative allosteric modulation of GABA A receptors containing alpha5 subunits.
- the present disclosure relates to a method for treating or ameliorating depression in a human subject comprising administering to the subject a therapeutically effective dose of a negative allosteric modulator of GABA A receptor (including a negative modulator of a GABA A receptor that has an alpha5 subunit, such as an inverse agonist of the alpha5 subunit-containing GABA A receptor) such as L-655,708; MRK-016; CP-457,920; RG-1662; a derivative or analog thereof; or a combination thereof in combination with one or more antidepressant drugs selected from the group consisting of monoamine oxidase inhibitors (MAOis), selective serotonin reuptake inhibitors (SSRis), serotonin-norepinephrine reuptake inhibitors (SNRis ), norepinephrine reuptake inhibitors (NRIs), modulators of CNS acetylcholine function, stimulants, antagonists of NMDA-type gluta negative allosteric
- the present disclosure relates to a method for treating or ameliorating depression in a human subject comprising administering to the subject a therapeutically effective dose of an inverse agonist of the alpha5 subunit-containing GABA A receptor, such as L-655,708; MRK-016; CP-457,920; RG-1662; a derivative or analog thereof; or a combination thereof, wherein the effective dose results in the presence of the inverse agonist in the cerebrospinal fluid at a concentration sufficient to bind 10 to 75% of all GABA A receptors and thereby reduce GABA A receptor function by 10 to 75%.
- an inverse agonist of the alpha5 subunit-containing GABA A receptor such as L-655,708; MRK-016; CP-457,920; RG-1662; a derivative or analog thereof; or a combination thereof
- the present disclosure relates to a method for treating or ameliorating depression in a subject comprising administering to the subject a therapeutically effective dose of one or more negative allosteric modulators of GABA A receptor (including a negative allosteric modulator of an alpha5 subunit-comprising GABA A receptor, such as an inverse agonist of the alpha5 subunit-containing GABA A receptor), such as L-655,708 or derivatives or analogs thereof (or MRK-16 or analogs or derivatives thereof; or CP-457,920, or analogs or derivatives thereof; or RG-1662 or analogs or derivatives thereof), or a combination thereof.
- a negative allosteric modulators of GABA A receptor including a negative allosteric modulator of an alpha5 subunit-comprising GABA A receptor, such as an inverse agonist of the alpha5 subunit-containing GABA A receptor
- L-655,708 or derivatives or analogs thereof or MRK-16 or analogs or derivatives thereof; or
- the effective dose of the negative allosteric modulator of GABA A receptor is administered to the subject every 0.5, 1, 2, 3, or more days or in repetitive dosing regimens. Repetitive dosing may occur when the modulator is provided alone or when it is provided with one or more other therapies, and when one or more other therapies are utilized with the modulator, the other therapies may be provided in repetitive dosing regimens.
- the present disclosure relates to a method for treating or ameliorating depression and/or suicidality in a human subject comprising administering to the subject a therapeutically effective amount of compound L-655,708; MRK-016; CP-457,920; RG- 1662; a derivative or analog thereof; or a combination thereof, in combination with another benzodiazepine binding site inverse agonist such as R04882224, R04938581 or other negative allosteric modulators of GABA A receptor function.
- another benzodiazepine binding site inverse agonist such as R04882224, R04938581 or other negative allosteric modulators of GABA A receptor function.
- the present disclosure relates to a method for treating or ameliorating depression and/or suicidality in a human subject comprising administering to the subject a therapeutically effective amount of compound L-655,708; MRK-016; CP-457,920; RG- 1662; a derivative or analog thereof; or a combination thereof, in combination with a 3-phenyl-5- arylpyridazine class of compounds such as RO 15-4513, RY-010, RY-023, RY-080, or RG- 1662.
- a 3-phenyl-5- arylpyridazine class of compounds such as RO 15-4513, RY-010, RY-023, RY-080, or RG- 1662.
- Embodiments of the disclosure include methods to reduce the risk of suicide in an individual prone to suicide and/or depression.
- a method of treating or preventing or ameliorating at least one symptom of a medical condition in an individual comprising the step of providing to the individual a therapeutically effective amount of one or more negative modulators of GABA A receptors, wherein the medical condition is selected from the group consisting of a depression- related disorder; an anxiety-related disorder; an attention-related disorder; a psychosis-related disorder; an eating disorder; a personality disorder; cognitive impairment following traumatic brain injury; neuropathic pain; chronic muscle or bone pain; diabetic complications resulting in nerve injury; generalized attack of muscular weakness; recurring sleep episodes during the day; migraine; addiction; suicidality; and a combination thereof.
- the onset of amelioration of one or more depression-related symptoms occurs within hours, days, or weeks.
- the GABA A receptor comprises an alpha5 subunit.
- the negative modulator may be selected from the group consisting of a negative allosteric modulators acting at the benzodiazepine binding site; negative allosteric modulators acting at the barbiturate steroid binding site; negative allosteric modulators acting at the neuroactive steroid binding site; competitive antagonists of the GABA A R; negative modulators acting in the pore of the GABA A R channel; nicotinamide and related compounds; inverse agonists and antagonists of the propofol binding site of the GABA A R; and a combination thereof.
- the depression-related disorder is major depressive disorder (MDD); dysthymia; cyclothymic disorder; seasonal affective disorder/seasonal depression; depression after traumatic brain injury; postpartum depression; premenstrual dysphoric disorder; depressive symptoms associated with menopause; depression following substance abuse/withdrawal; bipolar disorder; bipolar disorder in remission; or depressive episodes of bipolar disorder.
- the anxiety-related disorder is general anxiety disorder; obsessive compulsive disorder; Impulse control disorder; anxiousness associated with depression; repeated episodes of anxiety, extreme apprehension or fear of social interaction (social phobia); panic disorders; posttraumatic stress syndrome or posttraumatic stress disorder; or separation anxiety disorder.
- the attention-related disorder is attention deficit hyperactive disorder; or adult attention deficit hyperactive disorder.
- the psychosis-related disorder may be schizophrenia, schizophrenia- spectrum disorder or psychotic depressive illness, in some embodiments.
- the individual When the individual has an eating disorder, it may be anorexia nervosa; bulimia; or obesity.
- the individual has avoidant personality disorder; antisocial personality disorder; borderline personality disorder; conduct disorder; dependent personality disorder; depressive personality disorder; histrionic personality disorder; narcissistic personality disorder; negativistic personality disorder; obsessive- compulsive personality disorder; paranoid personality disorder; schizoid personality disorder; or schizotypal personality disorder.
- An individual treated with embodiments of the disclosure includes an individual that has been or has not been diagnosed with the medical condition.
- the negative modulator of GABA A receptor is a negative allosteric modulators acting at the benzodiazepine binding site; the negative modulator of GABA A receptor is a negative allosteric modulator acting at the barbiturate steroid binding site; the negative modulator of GABA A receptor is a negative allosteric modulator acting at the neuroactive steroid binding site; the negative modulator of GABA A receptor is a competitive antagonist of the GABA A R; negative modulator acting in the pore of the GABA A R channel; and/or the negative modulator of GABA A receptor is a partial inverse agonist of a GABA A receptor comprising an cc5 subunit.
- the partial inverse agonist of a GABA A receptor comprising an cc5 subunit is L-655,708, R04938581, CP-457,920, MRK-016, or a combination thereof.
- the method further comprises the step of providing to the individual a therapeutically effective amount of another therapy, such as one selected from the group consisting of monoamine oxidase inhibitors (MAOis), selective serotonin reuptake inhibitors(SSRis), serotonin-norepinephrine reuptake inhibitors (SNRis), norepinephrine reuptake inhibitors (NRIs), triple reuptake inhibitors, modulators of CNS acetylcholine function, stimulants, anti-glucocorticoids, antagonists of NMDA-type glutamate receptors, tricylic antidepressants (TCAs), and a combination thereof.
- the other therapy may be an antidepressant.
- FIG. 1 illustrates an example of ketamine's fast- acting therapeutic action and the involvement of excitatory synapses in depression.
- FIG. 2 Injection of L-655,708 produced a rapid increase in oscillatory activity In str. pyramidale of area CA1 (upper row) and the NAc shell (lower row) in vivo, particularly in the theta and beta frequency bands, that persisted for more than one hour.
- FIG. 3A In control slices (black), anpirtoline produced a fully reversible potentiation of TA-CA 1 EP8P slope of -175%. After CUS (gray), the potentiation was larger and persisted for >60min after washout.
- FIG. 3B In two slices from CUS rats given an injection of L-655,708 24 hours earlier, the potentiation was similar to controls.
- FIG. 4 24 hours after injection of L-655,708, but not vehicle, phosphorylation of S831 and total GluA 1 expression were increased in SLM of hippocampal tissue from CRS rats to levels comparable to unstressed controls. In contrast, L-655,708 had no effect in unstressed animals. [0044] FIG. 5. One hour after injection of L-655,708 there was an increase in expression of FosS and AFosB in unstressed animals in the NAc but not in the hippocampus. No changes were apparent 24hrs after injection.
- FIGS. 6A and 6B L-655,708 rapidly reverses loss of sucrose preference and social interaction behaviors after chronic restraint stress. Quantification of results from the sucrose preference test (SPT, FIG. 6A) and the social interaction tests (SIT, FIG. 6B) at two time points: before CRS and after 10 days of CRS. 24hrs prior to the second round of tests, rats received an injection of either vehicle (black, left bar in pairs of bars; vehicle) or L-655,708 (white, right bar in pairs of bars; L-655,708).
- FIGS. 7A, 7B, 7C, and 7D L-655,708 rapidly reverses loss of social interaction behaviors after chronic unpredictable stress but does not affect hedonic behavior in unstressed rats. Quantification of results from the social interaction test (SIT) at three time points: before CUS, after 4 weeks of CUS and a vehicle injection given 24 hrs earlier, and after an additional week of CUS and an injection of L-655,708 given 24 hrs earlier.
- SIT social interaction test
- FIG. 7B Analysis of individual animals revealed that 14 of 18 animals displayed robust responses to CUS and L- 655,708 (black). The 4 rats that failed to respond to L-655,708 appeared largely resilient to the effects of CUS (gray symbols). Unstressed controls were also given vehicle and L-655,708 injections at the same time points. Neither injection produced a significant change in social interaction (FIG. 7C) or sucrose preference (FIG. 7D).
- FIGS. 9A, 9B, and 9C MRK-016 rapidly reverses loss of sucrose preference and social interaction behaviors after chronic restraint stress.
- FIG. 9A Quantification of results from one group of rats in the sucrose preference test at five time points: baseline, after 2 weeks of CRS, 24hrs after an additional 3 days of CRS and 24hrs after injection of vehicle, after one week of CRS and 24hrs after an injection of MRK-016 (3 mg/kg), and in the same animals after an additional week of CRS and 7 days after the injection of MRK-016.
- FIG. 9B Results in individual animals for the full experiment.
- FIG. 10A representative traces showing the AMPAR- and NMDAR-mediated components of the fEPSP, recorded extracellularly in SLM of area CA1 in response to simulation of TA afferents in saline lacking added Mg2+. Traces are shown before (black) and after (gray) addition of 50 ⁇ DNQX to block AMPARs.
- FIG. 10B the mean slope of the relationship between AMPAR- (left) and NMDAR-mediated response (right) and FV amplitude over a range of stimulation intensities from the three groups of animals.
- FIGS. 11A and 11B L-655,708 rapidly reverses stress-induced decreases in GluAl expression at TA-CA1 synapses of the rat hippocampus.
- FIG. 11A Representative Western blots of GluAl and ⁇ -actin protein levels in SLM samples from unstressed rats (left) and rats subjected to 10 days of CRS then given an injection 24hrs earlier of either vehicle solution (middle) or L-655,708 (right).
- FIG. 11A Representative Western blots of GluAl and ⁇ -actin protein levels in SLM samples from unstressed rats (left) and rats subjected to 10 days of CRS then given an injection 24hrs earlier of either vehicle solution (middle) or L-655,708 (right).
- FIGS. 12A and 12B Neither stress nor L-655,708 injection affect time in the interaction zone in the target absent condition.
- FIG. 12A Percent time spent in the interaction zone is quantified for rats during the baseline period and 24 hrs after injection of either vehicle (white, right bar of pair of bars) or L-655,708 (black, left bar of pair of bars) for the experiments illustrated in FIG. 12A.
- FIG. 12B Percent time spent in the interaction zone is quantified for rats subjected to CUS (black, left bar of pair of bars) or unstressed rats (white, right bar of pair of bars) during the baseline period, 24 hrs after injection of vehicle, and 24hrs after injection of L- 655,708 for the experiments illustrated in FIG. 6B.
- therapeutic level refers to an amount or concentration of a compound or agent, e.g., a GABA A R antagonist, that achieves a therapeutic effect in a subject, wherein the therapeutic effect can be an amelioration, or alleviation, if not complete cessation, of one or more symptoms of clinical depression and other similar conditions, including suicidality as defined elsewhere herein.
- an effective dose is the dose of the compound that results in the presence of the compound in the cerebrospinal fluid at a concentration sufficient to bind to GABA A receptors, including those containing alpha 5 subunits.
- an effective dose is the dose of the compound that results in the presence of the compound in the cerebrospinal fluid at a concentration sufficient to bind to 10-75% of all GABA A Rs and thereby reduce GABA A R function by 10-75%, although in specific embodiments the percentages are 10-100%, 10-90%, 10-80%, 10-70%, 10-60%, 10-50%, 10- 40%, 10-30%, 10-20%, 20-100%, 20-90%, 20-80%, 20-70%, 20-60%, 20-50%, 20-40%, 20- 30%, 30-100%, 30-90%, 30-80%, 30-70%, 30-60%, 30-50%,, 30-40%, 40-100%, 40-90%, 40- 80%, 40-70%, 40-60%, 40-50%, 50-100%, 50-90%, 50-80%, 50-70%, 50-60%,, 60-100%, 60- 90%, 60-80%, 60-70%, 70-100%, 70-80%, 70-90%, 70-80%, 80-100%, 80-90%, 90-100,
- MDD Major depressive disorder
- ADs Monoaminergic antidepressants
- SSRIs selective serotonin reuptake inhibitors
- ADs Monoaminergic antidepressants
- SSRIs selective serotonin reuptake inhibitors
- Ketamine a noncompetitive NMDA receptor (NMDAR) antagonist, has demonstrated efficacy as a rapidly acting AD in treatment refractory patients.
- ketamine Low doses of ketamine result in a rapid and sustained improvement in core depressive symptoms and a decrease in suicidal ideation in individuals with treatment-resistant MDD (Berman et ah, 2000; Zarate et ah, 2006).
- ketamine exerts a rapid AD action in humans, its potential for use outside of the research setting is limited because it is addictive and because it produces dissociative, psychotomimetic effects even at low doses (e.g. Machado-Vieira et al., 2009).
- Ketamine has also provided a critical mechanistic insight into how rapid AD actions may be produced (e.g. Li et al., 2011), raising hopes that new drugs can be developed that lack its disadvantages and risks.
- ketamine The mechanism of ketamine' s fast-acting therapeutic action remains uncertain. It has been postulated that ketamine is somewhat selective for NMDARs on inhibitory interneurons, so that their excitation is diminished by ketamine, resulting in a mild disinhibition of the neuronal population and overall increase in its activity. Ketamine-induced increases in activity then cause stimulation of activity-dependent processes such as long-term potentiation and activation of the mammalian target of the rapamycin (mTOR) signaling pathway leading to the rapid induction of synaptogenesis via increased synthesis of synaptic proteins (Li et al., 2010) and restoration of normal activity.
- mTOR mammalian target of the rapamycin
- an alternative to ketamine as a rapidly acting AD includes partial inverse agonists of a5-containing GABA A RS.
- GABA A Rs are heteropentameric, ligand-gated ion channels.
- GABA A receptor subunits Nineteen GABA A receptor subunits have been identified to date. Most GAB A A receptors contain ⁇ , ⁇ , and ⁇ 2 subunits in a 2:2: 1 stoichiometry. ⁇ subunits direct membrane insertion whereas adjacent ⁇ 2 and a subunits form the benzodiazepine site, an allosteric modulator of channel gating. The identity of the a subunit determines the pharmacological profile of this site.
- Receptors containing al, a2, or a3 subunits are potentiated by Zolpidem, a benzodiazepine type 1 agonist, whereas receptors containing a5 subunits are essentially insensitive to Zolpidem.
- l subunits mediate the sedative, anticonvulsant and amnestic effects of benzodiazepines preferentially, whereas the a2 and a3 subunits mediate their anxiolytic effects.
- Partial inverse agonists offer the advantage of a wider therapeutic concentration range and a lower likelihood of producing anxiety or epileptiform discharge, in specific embodiments of the disclosure.
- a5-subunit mRNA is highly expressed in the pyramidal cells of the hippocampus and cortex (Allen Brain Atlas) and a5-containing GABA A receptors are localized in the dendrites of hippocampal CA1 pyramidal cells at synaptic and extrasynaptic sites. Because disinhibition promotes induction of long-term potentiation (LTP), and because of their selective forebrain localization, drugs that selectively inhibit a5-containing receptors are being developed as cognitive enhancers. It has been shown, for example, that partial inverse agonists of a5- containing GABA A receptors enhance associative memory acquisition in hippocampal-dependent learning tasks.
- LTP long-term potentiation
- one or more partial inverse agonists of the benzodiazepine binding site of GABA A receptors particularly those containing an a5 subunit, produce a rapid antidepressant action in unipolar and bipolar forms of depression and reduce suicidal ideation by restoring the normal function of excitatory synapses.
- Such considerations may be characterized, by example, using a rodent model of depression with face, construct, and predictive validity, chronic unpredictable stress (CUS) to compare the actions of acute administration (24 hrs) of the a5-selective partial inverse agonists (R04938581, Ballard et al, 2009; MRK-016, Atack et al, 2009) and the non-selective inverse agonist (FG7142; Shansky et al., 2004) with the actions of acutely administered ketamine.
- CCS chronic unpredictable stress
- Antidepressant efficacy of partial inverse agonists of a5 subunit-containing GABA A receptors are then tested in vivo using the sucrose preference and social exploration tests (Amat et al., 2010), for example.
- partial inverse agonists of a5 subunit- containing GABA A receptors exert an antidepressant action comparable to ketamine' s (Ibrahim et al, 2012).
- patients may undergo standard psychiatric screening for DSM-IV criteria for major depressive episodes.
- a saline solution comprising one or more of the agonists are provided to the individual, such as infused slowly (ca. 30-60 min), for example.
- Depression-related and other rating tests such as the Hamilton Depression Rating Scale, Beck Depression Inventory, Visual Analog Scales score for intoxication "high", and the Brief Psychiatric Rating Scale, may be given repeatedly; as an example only, they may be given over a four hour period after drug administration, and daily over the following seven days.
- Antidepressant efficacy, as well as psychotomimetic or anxiogenic responses, is determined upon changes in the test scores, in specific embodiments to show efficacy with a particular compound.
- the studies encompassed herein are the first to characterize the antidepressant- like efficacy of partial inverse agonists of a5 subunit-containing GABA A receptors. Rapid onset of antidepressant action, shown using established preclinical models, for example, is highly desirable from a clinical perspective and has never been attempted with these compounds. The studies allow one to demonstrate that partial inverse agonists of a5 subunit-containing GABA A receptors are useful at least as a treatment for depression.
- the medical condition may be diagnosed prior to treatment.
- the individual is suspected of having the medical condition, is at risk for having the medical condition, has shown behavior indicative of the medical condition, has a personal or family history of the medical condition, and so forth.
- symptoms of the medical condition may overlap with symptoms form other types of related medical conditions.
- depression-related disorders such as Major depressive disorder (MDD); dysthymia; cyclothymic disorder; seasonal affective disorder/seasonal depression; depression after traumatic brain injury; postpartum depression; premenstrual dysphoric disorder; depressive symptoms associated with menopause; depression following substance abuse/withdrawal; bipolar disorder; bipolar disorder in remission; and depressive episodes of bipolar disorder
- anxiety-related disorders such as general anxiety disorder; obsessive compulsive disorder;impulse control disorder; anxiousness associated with depression; repeated episodes of anxiety, extreme apprehension or fear of social interaction (social phobia); panic disorders; posttraumatic stress syndrome or posttraumatic stress disorder; and separation anxiety disorder
- attention-related disorders such as attention deficit hyperactive disorder; adult attention
- Embodiments of the disclosure provide for an improvement over other therapies in the art in cases wherein the treatment of the disclosure is effective with fewer doses than other therapies in the art.
- the individual is known to have or is suspected of having MDD (which is also known as clinical depression, major depression, unipolar depression, or unipolar disorder; or as recurrent depression in the case of repeated episodes), which is a mental disorder characterized by a pervasive and persistent low mood that is accompanied by low self-esteem and by a loss of interest or pleasure in normally enjoyable activities.
- MDD which is also known as clinical depression, major depression, unipolar depression, or unipolar disorder; or as recurrent depression in the case of repeated episodes
- MDD which is a mental disorder characterized by a pervasive and persistent low mood that is accompanied by low self-esteem and by a loss of interest or pleasure in normally enjoyable activities.
- the individual with MDD is suicidal, although in specific embodiments the suicidal person does not have depression.
- an individual may be suicidal who has one or more of the following attributes: depression; previous suicide attempts; preoccupation with death; making troubling or morose statements; talking openly about wanting to kill oneself; having developed a suicide plan; having acquired the means to carry out a suicide plan; "rehearsal" behavior; setting a time for a suicidal attempt; self- inflicted injuries, such as cuts, burns, and/or head banging; engaging in risky behavior, such as driving recklessly, using drugs and/or high-risk sexual behavior; making out a will or giving away favorite possessions; inappropriately saying goodbye, and so forth.
- the individual may be unipolar or bipolar.
- the individual may have a propensity for depression and/or suicidal thoughts because of a genetic or familial predisposition, for example, but not limited to, having the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and/or the transporter gene 5HTLPPR promoter region polymorphism.
- BDNF brain-derived neurotrophic factor
- condition being treated with methods and compositions encompassed by the disclosure is considered resistant to treatment with previously existing treatments for depression (including SSRIs, SNRIs and/or TCAs for example), such as treatment-resistant MDD, for example.
- the medical condition is diagnosed prior to treatment
- the individual is treated without formal diagnosis of the condition, such as in cases where a first responder, medical responder, family member, hospital worker, or so forth considers the treatment to be warranted.
- the individual may or may not be treated in a medical facility.
- the individual suffers from depression, has had one or more concussions or other brain injury, is being treated with a therapy (such as a drug) that has suicide and/or depression as a side effect, abuses alcohol or other prescription or recreational drugs, is a victim of mental and/or sexual abuse, a combination thereof, and so forth.
- the individual may be a professional athlete that has had one or more concussions, as an example.
- the individual may currently be in the military or may have been in the military.
- the individual may be of any race or gender or age.
- the treatment for the individual is considered to be effective in a shorter period of time than known treatment(s) for the condition.
- the individual may have a therapeutic effect within minutes, hours, days or weeks of the first administration.
- the individual is given the therapeutic composition(s) once or more than once.
- there are one or more therapeutic effects with the composition of the disclosure no more than days, hours, or minutes after the first administration.
- the therapeutic effect may take place no more than 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 day after the first administration.
- the therapeutic effect may take place no more than 96, 72, 48, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 hour after the first administration.
- the therapeutic effect may take place no more than 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minute after the first administration.
- a therapeutic effect may comprise a situation where the individual no longer wants to commit suicide, or has a reduced desire to commit suicide, or is having second thoughts about committing suicide, or is now uncertain about committing suicide, for example.
- a therapeutic effect may comprise when an individual no longer has depression or when the individual is less depressed or has fewer depression symptoms or has longer periods of time in between depressive moods, for example.
- the GABAA receptor comprises an alpha5 subunit.
- any such condition is treatable, in specific embodiments the condition has depression or suicidality as at least one symptom.
- administration of one or more compositions of the disclosure to the individual provides treatment of the condition or prevention of the condition and/or reduces the onset of the condition and/or reduces the severity of one or more symptoms of the condition.
- the composition utilized for methods of the disclosure includes one or more GABAA receptor negative modulators.
- GABAA receptor negative modulators may refer to compounds that decrease the activity of the GABAA receptor, e.g., by blocking or reducing the influx of chloride ions through the pore of the GABA A R (i.e. channel blockers), and/or by blocking or reducing binding of an agonist to the GABAAR (i.e. GABAAR antagonists) and/or blocking or reducing an effect of an agonist on the GABAAR (i.e. negative allosteric modulators).
- An exemplary GABAAR channel blocker is picrotoxin.
- Exemplary GABA A R antagonists include bicuculline and pentylenetetrazole.
- An exemplary GABA A R channel blocker is picrotoxin.
- Exemplary GABA A R negative allosteric modulators include non-selective and selective benzodiazepine receptor inverse agonists.
- GABAA receptor negative modulators are as follows: [0071] 1. Negative allosteric modulators acting at the benzodiazepine binding site. Beta- subunits direct membrane insertion whereas adjacent gamma2 and alpha subunits form the so- called benzodiazepine site, an allosteric modulator of channel gating. The identity of the a subunit determines the pharmacological profile of this site.
- GABA A R S containing alphal, alpha2 or alpha3 subunits are potentiated by Zolpidem, a benzodiazepine type 1 agonist, whereas GABA A Rs containing alpha5 subunits are essentially insensitive to Zolpidem (Burgard et al., 1996).
- alpha5- subunit mRNA is highly expressed in the pyramidal cells of the hippocampus and cortex (Allen rain Atlas) and alpha5 -containing GABA A Rs are localized in the dendrites of hippocampal CA1 pyramidal cells (Fritschy and Mohler, 199S; Wainwright et al., 2000) at synaptic and extrasynaptic sites (Serwanski et al. 2006). Because disinhibition promotes induction of long-term potentiation (LTP), and because of their selective forebrain localization, drugs that selectively inhibit alpha5 -containing receptors are being developed as cognitive enhancers (Ballard et al., 2009). It has been shown, for example, that partial inverse agonists of Cc5-containing GABA A Rs enhance associative memory acquisition in hippocampal-dependent learning tasks (Collinson et al., 2002).
- benzodiazepine binding site inverse agonists are as follows:
- Alpha5 subunit- selective the imidazo[l,5-a][l,2,4]-triazolo[l,5- d][l, ⁇ benzodiazepine class of compounds (such as R04882224, R04938581, L-655,708), the triazolophthalazine class of compounds (such as cc5IA), the 7,8,9, 10-tetrahydro-(7,10-ethano)- l,2,4-triazolo[3,4-a]phthalazine class of compounds, the pyrazolotriazine class of compounds (such as MRK-016), the 6,7-Dihydro-2-benzothiophen-4(5H)-one class of compounds, 6,6- Dimethyl-3-(2- hydroxyethyl)thio-l-(thiazol-2-yl)-6,7 -dihydro-2-benzothiophen-4(5H )-one, the 3,4-Dihydron
- Negative allosteric modulators acting at the barbiturate steroid binding site are drugs that were originally developed for their sedative properties. They act as positive allosteric modulators of GABA A Rs to increase the efficacy of GABA through an increase in channel open time. Barbiturates are thought to bind at the interface between an a and ⁇ subunit of the GABA A R (Sieghart et ah, 2012). Barbiturates at supra-clinical concentrations may also directly open the channel in the absence of GABA. Although negative allosteric modulators acting at this site have not yet been described, in specific embodiments they exert antidepressant actions and may or may not be selective for alpha5 subunit containing receptors.
- Neuroactive steroids are endogenous compounds that can be synthesized in the brain from cholesterol or steroidal precursors or by metabolism of adrenal steroids or gonadal steroids, such as testosterone (Mellon and Griffin, 2002).
- Examples of neuroactive steroids include pregnenolone and dehydroepiandrosterone, their sulfates, and their reduced metabolites.
- Allopregnanolone and tetrahydrodeoxycorticosterone are positive allosteric modulators of GABA A R-mediated chloride currents, whereas pregnenolone sulfate and dehydroepiandrosterone (DHEA) sulfate are negative allosteric modulators.
- Neuroactive steroids bind to the delta subunit of the GABA A R, which is expressed heavily in the forebrain and ventral striatum; brain regions implicated in the genesis of depression. There is evidence that pregnancy is associated with decreases in the expression of delta subunits and elevation of neurosteroid levels (Maguire et ah, 2009), in specific embodiments implicating dysregulation in their interactions as a contributing factor in post-partum depression.
- Drugs have been developed to mimic the positive allosteric effects of neuroactive steroids and are used clinically as sedatives and anesthetics, such as alphaxolone, alphadolone, hydroxydione and minaxolone. Because of the presence of endogenous neuroactive steroids in the brain, an antagonist of this site can also be predicted to weaken GABA A R-mediated inhibition. Because some selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, are reported to elevate levels of endogenous neuroactive steroids in the brain (Pinna et ah, 2006), in specific embodiments an antagonist at this site also amplifies the effects of such SSRIs. Drugs interacting at this site are useful in the treatment of postpartum depression, in specific embodiments.
- SSRIs selective serotonin reuptake inhibitors
- GABA A R antagonists are as follows: picro toxin, bilobalide, pentylenetetrazol, thujone, and ginkgolide B.
- Negative modulators acting in the pore of the GABA A R channel Numerous compounds have been developed that act to block the flux of CI- ions through the pore of the GABA A R. Because they do not compete with GABA at its receptor on the channel, they are referred to as noncompetitive antagonists (NCA).
- NCA noncompetitive antagonists
- the best known example is picro toxinin, which is also highly epileptogenic. Drugs active at this site are widely used as insecticides and act by physically blocking the channel, although allosteric modulation has not been ruled out.
- the ⁇ 3 subunit may be particularly relevant for NCA binding (Chen et ah, 2006). Low affinity blockers would be helpful for clinical utility.
- Nicotinamide and related compounds, as well as inverse agonists and antagonists of the propofol binding site of the GABA A R, are useful negative modulators of GABA A R-mediated inhibition, in specific embodiments.
- one or more negative modulators of GABA A receptors are utilized in therapeutic methods of the disclosure, for example to produce a robust antidepressant action in unipolar and bipolar forms of depression, in posttraumatic stress disorder, and in postpartum depression, by elevating mood and/or reducing suicidal ideation.
- the mechanism of action of these compounds is a strengthening of excitatory synapses that are pathologically weakened in depressed patients.
- these compounds act more rapidly than conventional antidepressants, such as inhibitors of monoamine neurotransmitter reuptake and catabolism.
- depression results from a pathological weakening of excitatory synapses in multiple brain regions affecting the function of reward circuits in the ventral midbrain, and the methods of the disclosure provide a therapy that addresses this physiological event.
- GABA A R negative modulators are given alone at a therapeutically effective dose.
- GABA A R negative modulators are given at a therapeutically effective dose together with one or more conventional antidepressant treatments.
- the conventional antidepressant(s) can be given (for example, orally) at current FDA-approved standard dosing regimens.
- GABA A R negative modulators are given at a therapeutically effective dose, fixed or varying, over an unlimited period of time to treat depression and related conditions.
- an individual is provided an initial dosing regimen that has a stronger dose of the treatment than a later dosing regimen that has a dose that is less than the initial dose.
- an individual is provided an initial dosing regimen that has a smaller dose of the treatment than a later dosing regimen that has a dose that is greater than the initial dose.
- GABA A R negative modulators are given at a therapeutically effective dose on a limited number of occasions (e.g., once per week or once every 2-3 days) for a limited period of time (e.g. , 1-4 months).
- the modulator may be given 1, 2, 3, or 4 or more times a day for a particular period of time, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months.
- Conventional antidepressant treatments may be given continuously, as per current dosing regimens approved by the FDA and other regulatory authorities. The depressive status of the individual may or may not be ascertained throughout the course of treatment.
- a GABA A R negative modulator acts on alpha 5 but also acts on other subunits of the GABA A R.
- one or more analogs or derivatives of a GABA A R negative modulator are utilized.
- One of skill in the art recognizes how to modify a modulator and test its activity in methods described elsewhere herein, such as in mouse models.
- the formulation of the one or more modulators is tailored toward the need of the individual. For example, in cases wherein an individual has a chronic depression problem, the formulation may need to be such that the amount in the individual is kept at a plateau, yet the modulator for an individual with imminent severe depression and/or suicide may need to be formulated so that it enters the bloodstream quickly.
- methods of the present disclosure for clinical aspects are combined with other agents effective in the treatment of one or more medical conditions encompassed by the disclosure.
- the present inventive therapy may precede or follow the other agent treatment by intervals ranging from minutes to days to weeks, for example.
- the other agent and composition(s) of the present disclosure are given separately to the individual, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the other agent and inventive therapy would still be able to exert an advantageously combined effect on the cell.
- an additional therapy is provided to the individual at the onset of treatment with methods and/or compositions of the disclosure, although the additional therapy may be provided before, during, and/or after the onset of treatment with methods and/or compositions of the disclosure.
- the individual may cease the treatment with methods and/or compositions of the disclosure once an additional therapy has been given to the individual, including for such a period of time that the additional therapy is able to be effective.
- one or more additional therapies other than those encompassed by the disclosure and in addition thereto are provided to the individual.
- the additional therapy may be for depression, suicidal tendencies, and so forth. Examples of conventional antidepressant drugs and treatment are provided below, and one or more of these may be employed with compositions of the disclosure. Doses are mg/day per os (p.o.) unless otherwise noted.
- Monoamine oxidase inhibitors include Selegiline -1.25-12mg/day; Tranylcypromine 10-60mg/day; Moclobemide 100-600 mg/day (reversible MAOI, approved outside the US); Phenelzine 15-90 mg/day; Isocarboxazid; and a combination thereof.
- Selective Serotonin reuptake inhibitors include Citalopram 10-20mg/day; Escitalopram 10-20mg/day; Fluoxetine 10-40mg/day, or 90mg/week slow release; Paroxetine 10-40mg/day; Sertraline 25-200mg/day; Fluvoxamine 50-300mg/day; and a combination thereof.
- Selective Serotonergic and Noradrenergic Reuptake Inhibitors include Venlafaxine XR 37.5-225 mg/d; Desvenlafaxine 50-100mg/day; Duloxetine 20- 120mg/day; Milnacipran 12.5-200mg/day; Levomllnacipran; Amoxaplne; Pro trip tyline; Nefazodone (moderate antagonist at 5HT-2 and alphal-adrenergic receptors); and a combination thereof.
- Stimulants include Methylphenidate 2.5-20 mg/day p.o., or 10- 30mg transdermal; Modafinil 100-400 mg; and a combination thereof.
- Examples of antagonists of NMDA-type glutamate receptors include ketamine 6.5-13mg/kg intramuscular injection, or 1-4.5 mg/l ⁇ g intravenous; Lanicemine (aka AZD6765 or AR-R15896AR); Memantine 5-20 mg/day; Amantadine 100-200 mg/day; Methoxetamine 6- lOmg/kg (NMDAR and serotonin reuptake); Riluzole 50mg/day; and a combination thereof.
- Tricyclic antidepressants include Desipramine 10-150 mg/day; Nortriptyline 10-100 mg/day; Amitriptyline 20-300 mg/day; Clomipramine 25-250 mg/day; Doxepin 10-300 mg/day; Imipramine 30-300 mg/day; Melitracen 10-225 mg/day; Amlneptine 25-250 mg/day; Opipramol 50-300 mg/day; Tianeptine 12.5-75 mg/day; Trimipramine 25-300 mg/day; and a combination thereof.
- Examples of other medications include Atomoxetine 40-100 mg/day (Strattera- selective norepinephrine only reuptake); Bupropion 75ql2h or 150-300/day; Buspirone (off- label) 10-30mg/day in multiple doses; Hypericum perforatum (St.
- John's wort-off-label 300- 3600mg/day; Lamotrigine XR 25-200 mg/day; Mirtazapine 7.5-45 mg/day; Trazadone 25-400 mg/day; L-triiodothyronine (off-label) 25-50 micrograms/day; Vilazodone 10-40 mg/day; Dexanabinol (HU-211) 150mg IV (cannabinoid-derived Immune modulator and NMDAR antagonist) Quetlapine (atypical antipsychotic); Ariprazole (atypical antipsychotic; often used in combination with other medications); and a combination thereof.
- Commonly used drug combinations include Chlordiazepoxide/Amitriptyline; Fluoxetine/Olanzapine; and Perphenazine/ Amitri, and one or more of the combinations may be employed with compositions of the disclosure
- Other interventions include Electroconvulsive therapy (ECT)- unilateral or bilateral; Transcranial magnetic stimulation (TMS) or repetitive TMS (rTMS) therapy; Psychotherapy (such as but not limited to problem-solving therapy; cognitive-behavioral therapy; interpersonal psychotherapy; psychosocial interventions (family-focused, interpersonal and social rhythms therapies) and Problem adaptation therapy (PATH), and one or more of the interventions may be employed with compositions of the disclosure.
- ECT Electroconvulsive therapy
- TMS Transcranial magnetic stimulation
- rTMS repetitive TMS
- PATH Problem adaptation therapy
- Exercise therapy (focusing on behavioral activation— a core concept of cognitive- behavioral therapy) may be employed and one or more types of exercise may be employed with compositions of the disclosure.
- compositions of the present disclosure comprise an effective amount of one or more compositions as disclosed herein dissolved or dispersed in a pharmaceutically acceptable carrier.
- pharmaceutically acceptable refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate.
- the preparation of a pharmaceutical composition that in some cases contains at least one negative modulator of a GABA A receptor of the invention, and in some cases an additional active ingredient, will be known to those of skill in the art in light of the present disclosure, as exemplified by Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, incorporated herein by reference.
- pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329, incorporated herein by reference). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplate
- composition(s) may comprise different types of carriers depending on whether it is to be administered in solid, liquid or aerosol form, and whether it needs to be sterile for such routes of administration such as injection.
- the present disclosure can be administered intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intramuscularly, intraperitoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally, topically, locally, injection, infusion, continuous infusion, localized perfusion bathing target cells directly, via a catheter, via a lavage, in lipid compositions (e.g., liposomes), as an aerosol, or by other method or any combination of the forgoing as would be known
- the actual dosage amount of a composition of the present invention administered to an individual can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, and the route of administration.
- the practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.
- compositions may comprise, for example, at least about 0.1% of a composition.
- the active compound may comprise between about 2% to about 75% of the weight of the unit, or between about 25% to about 60%, for example, and any range derivable therein.
- a dose may also comprise from about 0.1 mg/kg/body weight, 0.5 mg/kg/ body weight, 1 mg/kg/body weight, about 5 mg/kg/body weight, about 10 mg/kg/body weight, about 20 mg/kg/body weight, about 30 mg/kg/body weight, about 40 mg/kg/body weight, about 50 mg/kg/body weight, about 75 mg/kg/body weight, about 100 mg/kg/body weight, about 200 mg/kg/body weight, about 350 mg/kg/body weight, about 500 mg/kg/body weight, about 750 mg/kg/body weight, to about 1000 mg/kg/body weight or more per administration, and any range derivable therein.
- a range of about 10 mg/kg/body weight to about 100 mg/kg/body weight, etc. can be administered, based on the numbers described above.
- various dosing mechanisms are contemplated.
- the composition may be given one or more times a day, one or more times a week, or one or more times a month, and so forth.
- the composition may comprise various antioxidants to retard oxidation of one or more component.
- the prevention of the action of microorganisms can be brought about by preservatives such as various antibacterial and antifungal agents, including, but not limited to parabens ⁇ e.g., methylparabens, propylparabens), chlorobutanol, phenol, sorbic acid, thimerosal or combinations thereof.
- composition may be formulated in a free base, neutral or salt form.
- Pharmaceutically acceptable salts include the salts formed with the free carboxyl groups derived from inorganic bases such as for example, sodium, potassium, ammonium, calcium or ferric hydroxides; or such organic bases as isopropylamine, trimethylamine, histidine or procaine.
- a carrier can be a solvent or dispersion medium comprising, but not limited to, water, ethanol, polyol ⁇ e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), lipids ⁇ e.g., triglycerides, vegetable oils, liposomes) and combinations thereof.
- the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin; by the maintenance of the required particle size by dispersion in carriers such as, for example, liquid polyol or lipids; by the use of surfactants such as, for example, hydroxypropylcellulose; or combinations thereof such methods.
- isotonic agents such as, for example, sugars, sodium chloride or combinations thereof.
- isotonic agents such as, for example, sugars, sodium chloride or combinations thereof.
- Sterile injectable solutions are prepared by incorporating the instant invention in the required amount of the appropriate solvent with various amounts of the other ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and/or the other ingredients.
- the preferred methods of preparation are vacuum-drying or freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered liquid medium thereof.
- the liquid medium should be suitably buffered if necessary and the liquid diluent first rendered isotonic prior to injection with sufficient saline or glucose.
- the preparation of highly concentrated compositions for direct injection is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of the active agents to a small area.
- composition must be stable under the conditions of manufacture and storage, and preserved against the contaminating action of microorganisms, such as bacteria and fungi. It will be appreciated that endotoxin contamination should be kept minimally at a safe level, for example, less than 0.5 ng/mg protein.
- prolonged absorption of an injectable composition can be brought about by the use in the compositions of agents delaying absorption, such as, for example, aluminum monostearate, gelatin or combinations thereof.
- kits will thus comprise, in suitable container means, one or more compositions and, in some cases, an additional agent of the present invention.
- agents other than the composition of the disclosure such as one or more other agents for the treatment of depression or suicidal tendencies.
- kits may be packaged either in aqueous media or in lyophilized form.
- the container means of the kits will generally include at least one vial, test tube, flask, bottle, syringe or other container means, into which a component may be placed, and preferably, suitably aliquoted. Where there is more than one component in the kit, the kit also may generally contain a second, third or other additional container into which the additional components may be separately placed. However, various combinations of components may be comprised in a vial.
- the kits of the present disclosure also will typically include a means for containing the composition, additional agent, and any other reagent containers in close confinement for commercial sale. Such containers may include injection or blow molded plastic containers into which the desired vials are retained.
- compositions may also be formulated into a syringeable composition.
- the container means may itself be a syringe, pipette, and/or other such like apparatus, from which the formulation may be applied to an infected area of the body, injected into the individual, and/or even applied to and/or mixed with the other components of the kit.
- the components of the kit may be provided as dried powder(s).
- the powder can be reconstituted by the addition of a suitable solvent. It is envisioned that the solvent may also be provided in another container means.
- the kit may be configured such that it is easily used in or out of a medical facility setting, including in public, in an ambulance, in a home, or in a school, for example.
- the compounds may be orally active and/or self-administered, but could be infused intravenously, for example.
- individuals show an improvement in one or more standard assays of depression, such as the Hamilton Depression Rating Scale, Beck Depression Inventory, and/or the Brief Psychiatric Rating Scale, for example.
- Antidepressant efficacy, as well as any potential negative side effects, such as psychotomimetic of anxiogenic responses, may be readily apparent from changes in the test scores.
- Depression is a leading cause of mortality and morbidity worldwide. Severe depression affects as much as 5% of the US population, while 20% suffers from milder forms (Nestler et al., 2002). The annual economic burden of depression in the US is billions of dollars. Among the many devastating symptoms of depression, the prevalence of suicide (38,000 deaths/year) makes it a disease in desperate need of more effective therapeutic treatment. Despite its high incidence and socioeconomic impact, the etiology of depression remains poorly understood. Depression likely involves a combination of genetics (Flint and Kendler, 2014; Hamet and Tremblay, 2005) and environmental factors (Nestler et al., 2002). Many genes that increase risk for depression have been identified, but no single gene has strong penetrance.
- ADs Antidepressants
- SSRIs are effective in only about half of patients.
- 3-8 week delay between the onset of medication and the therapeutic effect complicates optimization of medication and delays symptomatic relief. A better understanding is needed in order to devise more effective therapies.
- Ketamine results in an AD-like behavioral response in rodents subjected to chronic stress (Maeng et al., 2008; Li et al. ,2011). Ketamine has also provided a critical mechanistic insight into how rapid AD actions may be produced (e.g. Li et al., 2011; Autry et al., 2011), raising hopes that new drugs can be developed that target the same signaling mechanisms, but lack ketamine's disadvantages and risks. [0125] Excitatory synapses and depression.
- VTA ventral tegmental area
- Chronic stress also weakens excitatory synapses within the prefrontal cortex (PFC)(Yen et al., 2012) and the hippocampus (Kallarackal et al., 2013), likely reducing afferent drive of the NAc and further decreasing the release of dopamine by rewarding stimuli.
- Chronic administration of fluoxetine restores the strength of hippocampal synapses and reverses stress-induced decreases in GluA 1 expression (Kallarackal et al., 2013).
- chronic stress promotes depression by weakening subsets of excitatory synapses in multiple brain regions that are critical in the determination of affect and reward. Depression results because the net effect of the weakened synaptic excitation is to impair activation of reward circuits ⁇ e.g. Nestler and Carlezon, 2005). Following this consideration, restoration of excitatory synaptic strength is a critical action of all effective antidepressants, in particular embodiments. [0127] Although it remains under active investigation, ketamine's fast-acting therapeutic action is consistent with the involvement of excitatory synapses in depression (FIG. 1).
- ketamine is somewhat selective for NMDARs on inhibitory interneurons (Moghaddam et al., 1997; Farber et al., 1998; Kavalali and Monteggia, 2012), such that ketamine decreases their excitation. This results in a mild disinhibition of the neuronal population and overall increase in high frequency oscillatory activity in animals ⁇ e.g. Kittleberger et al., 2012) and humans (Corn well et al., 2012). Presumably because of this increase in network activity, ketamine triggers several activity-dependent processes, such as long-term potentiation, increased expression of the immediate early gene deltaFosB, and activation of the mTOR and/or eEF2 signaling pathways.
- GABARS gamma-aminobutyric acid type-A receptors
- GABARS are heteropentameric ion channels, containing alpha, beta, and gamma subunits in a 2:2: 1 stoichiometry (Sieghart and Sperk, 2002).
- the interface between a gamma2 subunit and an a subunit forms the benzodiazepine receptor, a positive allosteric modulator of channel gating that increases GABAR function.
- drugs ⁇ e.g.
- beta- carboline that act as inverse agonists at the benzodiazepine site to decrease GABAR function.
- the molecular identity of the alpha subunit in the benzodiazepine receptor site determines its pharmacological profile.
- GABARs containing alphal subunits mediate the sedative, anticonvulsant and amnestic effects of benzodiazepines preferentially, whereas GABARs containing alpha2 and alpha3 subunits mediate their anxiolytic effects (Rudolph et ah, 1999; Mohler et ah, 2002).
- Partial inverse agonists offer the potential advantage of a wider therapeutic concentration range and a lower likelihood of producing negative side effects, such as anxiety or epileptiform discharge.
- Negative allosteric modulators of GABARs containing alpha5 subunits, or alpha5 GABA-NAMs have been developed recently (Quirk et al, 1996; Atack et al, 2006; 2009). Whereas non-selective benzodiazepine inverse agonists are anxiogenic in humans, alpha5 GABA-NAMs are not.
- alpha5- subunit mRNA is abundant in pyramidal cells in the hippocampus and cortex (Allen Brain Atlas) and cc5-containing GABARs are localized to synaptic and extrasynaptic sites in the dendrites (Fritschy and Mohler, 1995; Wainwright et ah, 2000; Serwanski et al. 2006).
- cc5-containing GABARs mediate tonic inhibition and lower the excitability of pyramidal cells (Bonin et ah, 2006).
- cc5 subunits are up-regulated in mice after chronic stress (Matsumoto et ah, 2007).
- alpha5 GABA-NAMs are being developed clinically as cognitive enhancers (Ballard et ah, 2009). It has been shown, for example, that alpha5 GABA-NAMs increase LTP and enhance memory acquisition in hippocampus-dependent learning tasks (Collinson et ah, 2002). Indeed, one alpha5 GABA-NAM compound is already in clinical trials for Down Syndrome. The ability of this class of compounds to promote excitatory drive in regions of the brain like the hippocampus indicates their utility as rapidly acting antidepressants, similar to ketamine but lacking the deleterious side effects.
- partial inverse agonists of the benzodiazepine binding site of GABA A receptors containing alpha5 subunits produce a rapid and persistent restoration of a range of behaviors that are impaired by chronic stress in rats and mice because they restore the strength of pathologically weakened excitatory synapses.
- Depression is a purely human condition, but behavioral changes can be induced in rodents in response to environmental conditions, like chronic stress, that promote depression in humans. Many of the behaviors affected by chronic stress, such as reward, are analogous to human behaviors that are symptomatic of human depression, such as anhedonia. Furthermore, susceptibility to several chronic stress paradigms is associated with genes known to have a high correlation with depression (Hasler et ah, 2004). It is important to assess validity in relating the effects of chronic stress in rodents to human depression.
- the behavioral and electrophysiological phenotypes of rodents subjected to chronic stress paradigms resemble human depression because they 1) include changes in affective state, cognition, and motivation; 2) result from a factor implicated in human depression; and 3) respond to chronic, but not acute, administration of SSRIs (Willner and Mitchell, 2002), as do the symptoms of depressed humans. Understanding how chronic stress affects the brain in rodents reveals insights into the genesis and treatment of human depression.
- Chronic stress paradigms One can use four different chronic stress paradigms in rats or mice to determine whether the effects of the compounds are paradigm-independent.
- CCS chronic unpredictable stress
- SDS chronic social defeat stress
- animals chronically lose social stature to a more dominant animal
- SDS protocol is repeated daily over 3 weeks.
- CRS chronic restraint stress
- animals are held in tight-fitting restraint tubes for 4h every day for 8-10 days
- corticosterone Gourley et ah, 2008
- All of these paradigms induce changes in animal behaviors that are reversed by chronic, but not acute, administration of SSRIs (Papp et ah, 1996; Grippo et ah, 2006; Bondi et ah, 2008), comparable to the 3-8 week delay in patients in response to SSRIs.
- sucrose preference test Another behavioral measure that is affected by chronic stress but is responsive only to chronic, but not acute, SSRIs is an assay of hedonic state called the sucrose preference test (SPT)(Rygula et al., 2006).
- SPT sucrose preference test
- rodents are presented with a two bottle choice task with one bottle containing normal water and one bottle containing a dilute sucrose solution.
- the naturally high preference of rats and mice for the sucrose solution is greatly diminished by chronic stress and restored with chronic, but not acute, SSRI treatment (Pothion et al., 2004).
- a lack of sucrose preference is said to reveal anhedonia, or the inability to experience reward, a core symptom of human depression. Defects in social reward are also a prominent symptom of human depression.
- One assay of rodents' social curiosity measures the amount of time animals spend interacting with a novel target animal and provides a measure of the rewarding value of social interactions.
- the hippocampus in depression depression is likely caused by dysfunction in many brain regions and cell types, including the hippocampus.
- Glucocorticoid receptors are expressed at high levels in pyramidal cells, rendering it particularly sensitive to stress (Reul & de Kloet, 1985; Magarinos et al., 1996). Indeed, chronic stress induces hippocampal dysfunction, including dendritic atrophy and spine Joss (McEwen, 1999), deficits in synaptic plasticity (Aifarez et al., 2003), decreased neurogenesis and synaptogenesis (Duman and Li, 2012), and aberrant circuitry (Airan et al., 2007).
- depressed patients have reduced hippocampal volume and deficits in hippocampus-dependent behavioral tasks (MacQueen et al., 2003; Campbell and MacQueen, 2004) such as visuospatial navigation (Hickie et al., 2005; Gould et al, 2007).
- Output from the hippocampus drives activity in the NAc, a key regulator of motivation and reward value, and is known to influence motivation, perhaps through its ability to promote dopamine secretion (Kelley and Mittleman, 1999; Boulenguez et al, 1996; Floresco et al, 2001; Tye et al, 2013).
- a dialogue between the hippocampus and the neocortex is also important for maintaining normal cognitive function (Gray, 1998; Lisman and Otmakhova, 2001; Morris et al, 1982; Remondes and Schuman, 2004).
- the entorhinal cortex (EC) provides the principal inputs to the hippocampus, and the projection from area CA 1 to the EC is a principal output.
- the apical dendrites of CA 1 pyramidal neurons in the hippocampus receive a direct EC input, the temporoammonic (TA) pathway, on their distal apical dendrites in stratum /acunosum molecular (SLM)(Remondes and Schuman, 2002; Steward & Scoville, 1976).
- the TA pathway is important for consolidation of long-term memory, as well as spatial recognition tasks (Brunei et al, 2002; Remondes & Schuman, 2004).
- Chronic stress produces a number of changes in TA- CA 1 excitatory synapses and deficits in memory consolidation (Cai et al, 2013; Kallarackal et al, 2013).
- This synapse as a convenient archetype for the changes that are known to occur at multiple sites in the brain in depression.
- mice are then retested with the SPT and SIT at 5, 10, and 15 days post-injection to determine the persistence of the effects.
- One set of control group of animals can undergo CRS, receive an injection of vehicle, and be tested with SPT and SIT at 1, 5, 10, and 15 days post-injection.
- a second set of control animals are not subjected to CRS, but receive an injection of the maximally effective dose of L-665,708 or MRK-016.
- the effects of the compounds are dose-dependent in both behaviors by both measures, and the effects persist for 5-15 days after injection.
- vehicle injection does not restore control responses in either behavior and the compounds do not affect either behavior significantly in unstressed animals.
- NSF Novelty suppressed feeding
- Conditioned place preference is a well-established assay of reward valuation and affective state. Therefore, a second cohort of animals undergoes the same procedure but is tested with a sexual place preference test. Control male rats are conditioned to associate sexually receptive females with specific olfactory and visual cues, then given a probe test of environmental preference (Camacho et ah, 2004). They are then subjected to CRS and susceptible animals selected. Half of the rats receive vehicle injection and the other half are given an injection of L-665,708. 24hrs later the place preference probe test is repeated. For both cohorts, two way comparisons are then made between behavioral scores (before vs. after injection x drug vs. vehicle).
- dominant animals lose their dominance as a consequence of stress. If so, one can administer an injection of L- 665,708 or vehicle.
- dominance is restored by alpha5 GABA-NAM, but not vehicle, injection in parallel with sucrose preference. Controls are treated as above, but not subjected to CRS. 24hrs later they are retested in the sucrose preference, urine marking, and tube tests.
- a third cohort of control rats receive an injection of L-665,708 or vehicle then undergo forced swim tests 1 hr later.
- Statistical comparisons of time spent immobile are made between vehicle and drug injected animals.
- Acute ketamine reduces immobility time in the forced swim test (Maeng et ah, 2008), much like acute fluoxetine administration, indicating that the alpha5 GABA-NAM compounds also decrease immobility in this test.
- CI One cohort of control rats are given a baseline open field test. One week later, half of the animals receive an injection of L-665,708 or vehicle, followed 24hrs later by a second open field test in a new arena.
- a mixed design analysis of variance reveals no difference of either alpha5 GABA-NAM or vehicle injection on the amount of time spent in the center zone, an indicator of anxiety, or in total line crossings, an indicator of locomotion, compared to either their own baseline or across groups.
- C2 A second cohort is tested for altered daily activity rhythms, as an initial indicator of altered sleep. Rats are housed singly in a cage with multiple crossed infrared beams (SmartCage, Afasci, Inc). Frequency of beam breaks is recorded continuously over a 48hr-period prior to an injection of L-665,708 or vehicle. Activity is then recorded over the following 48hrs. Total number of beam breaks and the duration of periods of inactivity are compared in individual animals before and after injection, and between treatment and vehicle groups in another mixed ANOVA.
- Dl One cohort of controls experience social defeat daily for lhr each day for 3 weeks.
- Another cohort of controls receives corticosterone hemisuccinate (50 g/ml) via the drinking water in their home cage for 4 weeks, to produce elevated blood concentrations correlating with the animals' diurnal cycle. Previous studies have shown that peak levels are comparable to those elicited in rats during chronic stress procedures (Gourley et ah, 2008). Susceptible rats in each group then undergo another week of SDS or corticosterone administration. Half of the rats in each group receive an injection of L-665,708 and half vehicle. 24hrs later they again undergo SPT and SITs.
- sucrose preference and social interaction ratios are made for individuals before and after vehicle or drug injection in a mixed design ANOVA.
- injection of the test compound, but not the vehicle produces a significant change in the animals' sucrose preference and social interaction ratios in both SDS and corticosterone-treated rats.
- alpha5 GABA-NAM antidepressant-like restorative actions on stress-sensitive behaviors are highly generalizable across a range of the motivational behavioral phenotype (feeding, social, sexual) and whether they are independent from the means in which the stress was applied (direct vs. physical vs. social).
- a useful antidepressant compound is broadly effective, regardless of the proximate cause of the altered behavior, and has few side effects.
- Ketamine induces a rapid increase in neural oscillations in circuits in the hippocampus, entorhinal cortex, NAc, and PFC in rodents (e.g. Kittleberger et al, 2012; Middleton et al., 2008; Hunt et al., 2011) and in humans (Driesen et al., 2013). It is widely accepted that this increase in circuit activity underlies the induction of ketamine's antidepressant- like actions because oscillatory activity at these frequencies promotes not only LTP (e.g. Huerta and Lisman, 1993) but also other forms of activity-dependent strengthening of excitatory synapses that are critical to the reversal of the stress phenotype.
- LTP e.g. Huerta and Lisman, 1993
- alpha5 GABA-NAM' s ability to reverse the stress phenotype results from triggering similar oscillatory activity.
- alpha5 GABA-NAMs bind to benzodiazepine receptors to induce rapid activation of neural circuits in the reward circuitry and restore stress-altered behaviors because of their ability to activate activity-dependent synaptic plasticity.
- Bl One can use Petlcre-Lmxlbflox mice (Zhao et ah, 2006), in which adults lack any serotonergic neurons in the CNS, to characterize this. Surprisingly, these mice have not yet been characterized in many depression-related behaviors, but it is possible that these behaviors are abnormal.
- SPT and SIT One can first characterize these mice in the SPT and SIT. If their behavioral responses are within the same range as wild type littermate mice, then one can subject them to 10 days of CRS. One week later, they receive a single injection of L-665,708 or vehicle, followed 24hrs later by a second round of SPT and SIT.
- alpha5 GABA-NAMs restorative action on these behaviors is independent of serotonin release and serotonin receptor activation.
- L-655,708 triggers an increase in both measures so that they are different compared to levels before drug injection in repeated measures comparisons, whereas in certain embodiments vehicle-treated animals do not have different measures in a mixed ANOVA design. If these mice do not have sucrose preferences >75 and social interaction ratios >130 , then one does not pursue the experiments further.
- One can select control and CRS susceptible rats Half of the susceptible rats are injected twice with the toxin PCPA (300 mg/kg- , IP, 24hrs apart)(Dewar et ah, 1992) to deplete serotonin acutely. The other half is injected with saline. 24hrs after the second PCPA injection, both sets of rats are given a single injection of L-665,708. 24hrs later they are given SPT and SITs. Animals are sacrificed and sections stained with an antibody against serotonin to verify PCPA-induced serotonin depletion, as has been done previously (Cai et ah, 2013).
- alpha5 GABA-NAMs act independently of serotonin, in specific embodiments both PCPA- and saline-injected rats show normalization of stress-sensitive behaviors in response to alpha5 GABA-NAM treatment.
- Experiment C Do alpha5 GABA-NAM's actions depend on NMDAR-dependent plasticity or GluAl phosphorylation? Ketamine's actions probably depend on blockade of interneuron NMDARs, with the subsequent increase in activity driving strong activation of pyramidal cell NMDARs.
- FOG. 1 effector mechanism
- CxNRIKO mice Iwasato et al, 2000
- NMDARs are genetically deleted in hippocampal and cortical pyramidal cells.
- These mice are also uncharacterized in many depression-related behaviors and it is possible that these behaviors are abnormal (see however: Rompala et al., 2013).
- alpha5 GABA-NAM's restorative action on these behaviors is dependent on pyramidal cell NMDAR receptor activation and therefore, in the absence of these NMDARs, alpha5 GABA-NAMs are unable to restore stress-induced behavioral changes.
- Paired comparisons in either alpha5 GABA-NAM - or vehicle-injected rats reveal no significant differences in sucrose preference or social interaction compared to before injection, in specific embodiments. If these mice do not display responses in the normal range of responses in SPT and SIT under control conditions, then one can administer a single injection of L-665, 708 or vehicle at the maximal dose, followed by a second round of SPT and SIT 24hrs later.
- alpha5 GABA-NAM is effective in the CxNRIKO mice; in which NMDARs in the NAc are not deleted, then in specific embodiments activation of inputs from the cortex and hippocampus by alpha5 GABA-NAM are crucial in its AD-like actions.
- mice One can next use S831A mice in which serine 831 of the GluAl subunit of the AMPAR has been mutated to alanine, rendering them incapable of being phosphorylated by CaM kinase.
- NMDAR-dependent L TP is abnormal in these mice (Lee et al., 2010). These mice have a behavioral phenotype that resembles that produced by chronic stress, although social interaction was not yet tested.
- Hippocampal brain slices may be harvested upon completion for electrophysiological and biochemical analyses, as described below, to test correlations between behavior and synaptic function.
- alpha5 GABA-NAM's antidepressant-like restorative actions on stress-sensitive behaviors 1) are induced by a benzodiazepine receptor-dependent increase in oscillatory circuit activity and 2) require NMDAR-dependent activity-dependent strengthening of excitatory synapses for their expression.
- AMPAR-mediated responses are compared using two independent methods (fiber volley amplitude and NMDAR-mediated responses) to control for the intensity of stimulation and the health of the slices, as has been done previously (Kallarackal et ah, 2013).
- Schaffer collateral responses are measured as a control because they are not affected by chronic stress by this measure (Kallarackal et ah, 2013).
- AMPAR-mediated excitation is decreased in slices from vehicle-injected CRS rats compared to unstressed, vehicle-injected controls. Injection of alpha5 GABA-NAMs restores control levels of excitation in slices from CRS rats, but has no effect in control rats. This is what has been observed in initial studies (FIG. 10A, IOC).
- Experiment B Do alpha5 GABA-NAMs restore 5-HTlBR-mediated potentiation?
- alpha5 GABA-NAMs reverse another phenotypic alteration of stressed TA-CA 1 synapses: amplification and persistence of responses to the 5- HT1BR agonist anpirtoline (FIG. 3A)(Cai et ah, 2013).
- Slices are prepared from the four groups described in Experiment A.
- Anpirtoline (50 ⁇ ) is bath applied for 60min, followed by a 90min washout period.
- anpirtoline potentiation of TA-CA 1 fEPSPs is of a larger magnitude and is persistent in slices from vehicle-injected CRS animals compared to unstressed, vehicle-injected controls and that injection of alpha5 GABA-NAM restores control levels of reversible potentiation in slices from CRS rats, but has no effect in control rats (see FIG. 3B).
- expression of GluAl and PSD-95, but not GluA2 or NR1 is decreased in the SLM in vehicle- injected CRS animals compared to unstressed, vehicle-injected controls and injection of alpha5 GABA-NAM increases GluAl S831 phosphorylation and restores control levels of expression in CRS rats, but has no effect in control rats (see FIG. 3).
- Tissue punches are taken from the NAc, area CA 1 (separating dendritic and somatic layers), the EC, and the PFC and subjected to Western blotting for quantification of BDNF and phosphorylated and total eEF2 expression, as in Autry et al. (2011 ). If dephosphorylation of eEF2 contributes to alpha5 GABA-NAM' s actions, then in specific embodiments phosphorylated eEF2 decreases and BDNF increases in tissue from alpha5 GABA- NAM-injected rats, compared to tissue from vehicle-injected rats. In the hippocampal samples, the changes in phospho-eEF2 and BDNF are greater in dendritic tissue than in somatic tissue. [0178] D3.
- Tissue punches are taken from the NAc, area CA1, EC, and PFC and subjected to Western blotting for quantification of deltaFosB levels. Sections are prepared from these same regions and stained for AFosB in order to count immunoreactive nuclei with stereological techniques (Vialou et ah, 2010). Sections through the ventral striatum are co-stained with an antibody against the D1R, since the expression of AFosB in these cells may be particularly important for SSRI actions (Lobo et a/., 2013). Similar to fluoxetine, in specific embodiments in stressed and unstressed animals, alpha5 GABA-NAM affects AFosB expression in the NAc and other brain regions, consistent with initial studies (FIG. 5).
- alpha5 GABA-NAM' s rapid reversal of stress- induced behavioral phenotype is accompanied by rapid changes in the stress-induced synaptic phenotype.
- partial inverse agonists of the benzodiazepine site of GABARs containing cc5 subunits have antidepressant efficacy.
- stress-induced synaptic changes cause stress-induced behavioral changes.
- there is mapping of specific synapses affected by stress and the corresponding behavioral consequence of that dysfunction such as the correlation between TA-CA1 synaptic strength and memory consolidation (Kallarackal et ah, 2013).
- 5-HTlBRs potentiate TA-CA1 synapses by a strengthening of postsynaptic AMPAR responses mediated by phosphorylation of AMPARs by CaMK (Cal et al, 2013).
- Another parallel signaling pathway, involving ras and activation of ERK is also activated. Inhibition of ERK blocks 5-HTlBR-mediated potentiation by preventing CaMK from being able to phosphorylate GluAlRs.
- the magnitude of 5-HTlBR-induced potentiation at TA-CA1 synapses is greater after CUS and in specific embodiments this was because of a low initial strength of excitatory synapses (Cal et ah, 2013). This was confirmed with electrophysiology and biochemistry (Kallarackal et ah, 2013).
- 5HTlBR-mediated potentiation is also persistent in slices from CUS animals, unlike controls, and this is mediated by a persistent phosphorylation of S831 of GluAlRs.
- phosphorylation of S845 in GluRl subunits iss critical and. One can compare changes in S845 phosphorylation in control and CUS tissue. Administration of corticosterone is necessary and sufficient to mimic both of these consequences of CUS.
- S831A transgenic mice but not 5-HT1BR knock-out mice, were anhedonic even in the absence of CUS, supporting a model of depression in which cognitive and emotional disturbances result from a dysfunction of excitatory synapses, rather than a dysfunction of serotonergic signaling (Cai et al., 2013; Kallarackal et al., 2013).
- alpha5 GABA-NAM L-655,708 and MRK-0106 are dissolved in DMSO and then diluted in saline for injection.
- Sucrose preference and novelty suppressed feeding tests were as described in Cai et al. (2013).
- Test rats are first placed alone for 3 min in an arena with a small holding pen at one end empty, then removed for 60 min and placed back in the arena with a novel juvenile rat in the holding pen.
- Video recordings are made of the position of the rat in the arena and then analyzed post-hoc to compute an interaction ratio, defined as the ratio of the time the rat spends in an 'interaction zone' near the holding pen with the juvenile present and absent (Berton et ah, 2006). Multiple SITs are performed >5 days apart.
- Rats are housed as pairs and receive 2 training sessions in which they are placed at one end of a lm long, 5cm diameter tube, with a food reward at the far end. Ten times per day for 5 days, they are placed at opposite ends of the tube. The rat that comes out at the opposite end of the tube is declared the winner. A score is assigned to each rat in the pair based on the number of aggregate wins. Only pairs in which one rat wins > 75% of trials are considered to have a sufficiently strong dominance to test the effects of CRS.
- Urine scent marking Rat pairs are placed in opposite sides of a cage divided by a screen with sheets of filter paper underneath. Dried sheets are stained with ninhydrin, which stains amines in urine, and photographed. The number and area of the marks are quantified using ImageJ (Lehmann et ah, 2013).
- Alpha5- selective negative allosteric modulators of GABAA receptors exert a rapid antidepressant action and restore stress-induced impairment of excitatory synaptic strength
- SSRIs Selective serotonin reuptake inhibitors
- NMDA receptor antagonist ketamine exerts a rapid antidepressant action, but has troubling side-effects.
- partial inverse benzodiazepine agonists would exert similar effects on brain activity as ketamine, but would not exert as many side effects if targeted only to GABA A receptors containing alpha5 subunits, which are enriched in the hippocampus and prefrontal cortex.
- L-655,708 reversed the alterations in hedonic behavior in the sucrose preference and social interaction tests produced by two different chronic stress paradigms in rats within 24 hrs of systemic administration.
- L-655,708 had no effect on hedonic behavior in unstressed animals.
- L-655,708 injection also restored within 24 hrs the strength of pathologically weakened excitatory synaptic transmission at the stress-sensitive temporoammonic-CAl synapse, measured electrophysiologically, and increased levels of GluAl subunit of the AMPA receptor, measured with Western blotting.
- the ability of L-655,708 to restore excitatory synaptic strength rapidly underlies its ability to restore stress-induced behavioral alterations rapidly, supporting evidence that dysfunction of multiple excitatory synapses in cortico- mesolimbic reward pathways contributes, in part, to the genesis of depression.
- Partial inverse agonists of the benzodiazepine receptor site of a5 subunit-containing GABA A receptors are useful as rapidly acting and clinically viable antidepressant compounds.
- SSRIs selective serotonin reuptake inhibitors
- NMDARs NMDA-type glutamate receptors
- Ketamine also produces a rapid antidepressant- like behavioral response in rodents subjected to chronic stress (Maeng et ah, 2008; Autry et ah, 2011; Li et ah, 2010; 2011). This has provided critical mechanistic insights into how rapid antidepressant actions may be produced and raised hopes that new drugs can be developed that target the same effector mechanisms, without ketamine' s disadvantages.
- a common element linking the therapeutic actions of antidepressants including SSRIs (Cai et al., 2013), ketamine (Pittenger and Duman, 2008; Kavalali and Monteggia, 2012; Abdallah et al., 2014), and scopolamine (Voleti et al., 2013), is their shared effects on excitatory synapses in cortico-mesolimbic reward circuits.
- Chronic stress produces depression-like changes in behavior as well as deleterious effects on excitatory synaptic structure and function in multiple brain regions that are associated with cognition, reward, and mood, including the hippocampus (McEwen, 2000; Kallarackal et al, 2013), prefrontal cortex (PFC)(Yuen et al, 2012; Pittenger and Duman, 2008), and nucleus accumbens (NAc)(Lim et al, 2012).
- hippocampus McEwen, 2000; Kallarackal et al, 2013
- prefrontal cortex PFC
- NAc nucleus accumbens
- ketamine, serotonin, and SSRIs promote excitatory synaptic transmission and reverse the effects of chronic stress in these same areas (Pittenger and Duman, 2008; Li et al., 2010; Autry et al., 2011; Cai et al, 2013).
- ketamine administration triggers several activity-dependent processes, such as induction of long-term potentiation, increased expression of the immediate early gene deltaFosB, and altered activity of the mTOR and/or eEF2 signaling pathways.
- activity-dependent processes such as induction of long-term potentiation, increased expression of the immediate early gene deltaFosB, and altered activity of the mTOR and/or eEF2 signaling pathways.
- GABA A RS ⁇ -aminobutyric acid type-A receptors
- GABA A Rs containing the a5 subunit are exclusively expressed by prefrontal cortical neurons and hippocampal pyramidal cells, offering the means for selectively targeting cortical inputs to mesolimbic circuits, thereby minimizing psychotomimetic and sedative side effects.
- L-655,708 is one such partial inverse agonist of GABA A R benzodiazepine sites with a 10-100 fold selectivity for GABA A Rs containing the alpha5 subunit (Atack et al, 2005; 2006). alpha5- selective inverse agonists of the benzodiazepine site are not epileptogenic, hallucinogenic, or anxiogenic in humans (Atack et ah, 2009).
- L-655,708 would exert a rapid antidepressant action via convergence on ketamine's downstream effector mechanisms, and therefore predicted that a single treatment of L-655,708 would rapidly ( ⁇ 24 hrs) reverse chronic stress-induced changes in both hedonic behavior and excitatory synaptic transmission at the archetypical stress-sensitive synapse between temporoammonic (TA) afferents and the distal dendrites of CA1 pyramidal cells.
- TA temporoammonic
- Harlan Laboratories were placed in appropriately sized restraint tubes, highly restricting their movement for periods of four hours in a brightly lit lab, every day for ten days during the light phase of their diurnal cycle (Lim et ah, 2012).
- CUS Chronic unpredictable stress
- Sucrose preference test SPT. Rats were given a choice between two bottles containing tap water or a 1% sucrose solution (Rygula et ah, 2006). Testing was conducted overnight (16 hours), including the full duration of their dark phase. Animals were first trained with both bottles while group-housed. For subsequent tests, including during the baseline period, animals were individually housed. Sucrose preference was calculated as amount of the sucrose solution consumed as a percentage of the total amount of liquid consumed. For determining the effects of L-655,708, only unstressed rats that demonstrated a sucrose preference >75 at baseline were used. [0213] Social interaction test (SIT).
- rats were placed in a plastic enclosure (82 x 82 cm) with a 5x5 grid of squares (16.4 x 16.4 cm) visible underneath the clear plastic flooring.
- a small translucent perforated plastic box (20 x 16 cm) was placed against the center of one wall of the arena.
- white overhead fluorescent lighting was used to illuminate the arena.
- a video camera positioned 170 cm above the floor of the arena was used to track the movements of the rats during the experiment.
- Each test consisted of a "target- absent” trial followed by a "target-present” trial.
- an individual test rat was placed in the center of the arena and, after 30s of adaptation, the rat's movements were recorded with the video camera for 2.5 minutes.
- the test rat was removed from the arena and placed back in its home cage.
- a novel juvenile (3-6 weeks old; always younger than the rat being tested) rat was placed in the internal box at one end of the arena and, after three minutes, the test rat was returned to the center of the arena and filmed for 2.5 minutes. Both rats were removed and the testing arena and internal box were cleaned with 70% ethanol before the next rat was tested. No test rat ever encountered the same target rat more than once.
- Results were quantified as the percentage of time spent in the "interaction zone” (the five grid squares immediately surrounding the plastic cage) as measured for both the "target- absent” and “target-present” trials. These percentages were then used to calculate an interaction ratio, which is the percent time spent in the "interaction zone” during the "target-present” trial divided by that of the "target-absent”.
- Acute slice electrophysiology Standard methods were used to prepare 400- ⁇ - thick transverse hippocampal slices. Dissection and recording saline contained: 124 mM NaCl, 3 mM KC1, 1.25 mM NaH 2 P0 4 , 1.5 mM MgS0 4 , 2.5 mM CaCl 2 , 26 mM NaHC0 3 , and 10 mM glucose, bubbled with 95% 02/5% C0 2 . Slices were then transferred to a submersion-type recording chamber and perfused at 0.5 - 2 ml/min at 20-22°C.
- Picrotoxin (100 ⁇ ) and CGP52432 (2 ⁇ ) were included to block GAB A A and GABA B receptors, and the CA3 region was removed with a scalpel. Because TA-CA1 synapses are electrotonically remote from CA1 cell somata, extracellular recording of local field excitatory postsynaptic potentials (fEPSPs) was used. Recording pipettes (3-5 ⁇ ) contained extracellular saline and were placed in stratum lacunosum-moleculare (SLM) to record TA-CA1 responses. fEPSPs were amplified 1000X, filtered at 3 kHz, and digitized at 10 kHz. Concentric bipolar tungsten electrodes were placed >500 ⁇ from the stimulating electrodes in SLM for TA afferents. Stimuli (100 ⁇ 8) were delivered at 0.05 Hz.
- SLM stratum lacunosum-moleculare
- Mg2+-free saline was used to produce a robust NMDAR-mediated component of the fEPSP for quantification of AMPAR- mediated synaptic excitation.
- 3-5 consecutive responses were averaged and fEPSP slope was calculated over a 1-3 ms window.
- the window was fixed in the initial rising phase of the response, 2-5 ms after its initiation.
- DNQX 50 ⁇ was bath applied for 15 min and the slope was calculated over a 3-5 ms window in the rising phase of the response, 5-10 ms after its initiation.
- L-655,708 was purchased from Tocris Bioscience (R&D Systems, Minneapolis, MN) and prepared at a concentration of 5mM in 75% saline/25% DMSO. The dose used in this study (0.7 mg/kg i.p.) was taken from the study of Martin et al (2009), in which L- 655,708 was shown to reverse the amnestic properties of the anesthetic etomidate; a positive sign of its efficacy in brain. This dose is sufficient to occupy about 70% of forebrain binding sites (Atack ei al., 2005)
- 24 hrs after a single injection of L-655,708 social interaction in 14 of 18 CUS rats were reversed to levels that were not significantly different than pre-stress baseline or responses in unstressed animals (FIG. 7B, black symbols).
- the four CUS rats injected with L-655,708 that failed to display an increase in social interaction appeared largely resilient to the CUS procedures (FIG. 7B, gray symbols).
- Chronic stress induces a reduction in excitatory synaptic transmission in many cortico-mesolimbic nuclei, including TA-CA1 synapses in the hippocampus (Kallarackal et ah, 2013).
- Chronic, but not acute, administration of fluoxetine restores their strength with a time course that is comparable with behavioral restoration (Cai et ah, 2013). Therefore, TA-CA1 synaptic transmission was examined to ask whether L-655,708 would reverse a stress-induced synaptic phenotype as rapidly as it reversed stress-induced behavioral changes.
- the inventors used extracellular electrophysiological recording of fEPSPs at TA- CA1 synapses in SLM of area CAI in brain slices prepared from unstressed rats, rats subjected to ten days of CRS and given a vehicle injection 24 hrs earlier, and rats subjected to ten days of CRS and given an L-655,708 injection 24 hrs earlier (0.7 mg/kg, i.p.). These were the same rats used for the behavioral analyses in FIG. 6. fEPSPs were recorded in ACSF lacking added Mg2+ so as to unblock NMDA receptors.
- the slope was first quantified of the AMPAR component of the fEPSP elicited over a range of stimulation intensities as a function of the amplitude of the fiber volley (FV), a measure of the number of synapses activated.
- DNQX was then applied to block AMPAR-mediated transmission and elicited a series of NMDAR-mediated responses over the same range of stimulation intensities, as in a previous study (Kallarackal et ah, 2013).
- An AMPA:NMDA ratio was computed for each slice using the slope of the response elicited when the FV was ca. 0.2 mV in amplitude before and after application of DNQX.
- SLM tissue was harvested from slices taken from unstressed rats, rats subjected to ten days of CRS and given a vehicle injection 24 hrs earlier, and rats subjected to ten days of CRS and given an injection of L-655,708 24 hrs earlier (0.7 mg/kg, i.p.). These were the same rats used for FIG. 6.
- L-655,708 a partial inverse agonist at the benzodiazepine site of the GABA A R that is highly selective for receptors containing alpha5 subunits, reverses the behavioral and synaptic phenotypes produced by two different chronic stress paradigms within 24 hrs of a single systemic administration.
- the motivated, appetitive behaviors assayed in the social interaction and sucrose preference tests assay the hedonic properties of two distinct stimuli, food and sociality.
- rats In both the sucrose preference and social interaction tests, rats must respond in an active manner to display the high levels of sucrose preference and social interaction that are normally observed.
- Chronic stress is known to decrease the rewarding properties of a variety of natural and unnatural stimuli in rodents, including their high preference for palatable sucrose-containing solution (Pothion et ah, 2004) and the naturally rewarding value of social interactions (Berton et ah, 2006).
- the loss of the rewarding properties of these stimuli is considered to be analogous to anhedonia, or the inability to experience reward, a core symptom of human depression.
- alpha5 -containing GABA A receptors as an antidepressant drug target.
- GABA A receptors are heteropentameric ion channels, most commonly containing alpha, beta, and gamma subunits in a 2:2: 1 stoichiometry (Sieghart and Sperk, 2002).
- the interface between a gamma2 subunit and an a subunit forms the benzodiazepine receptor, a site of allosteric modulation that alters channel gating and GABA A R function.
- benzodiazepine agonists positive modulators
- there are inverse agonists that act at the benzodiazepine site to decrease GABA A receptor function negative modulators.
- the molecular identity of the a subunit in the benzodiazepine receptor site determines its pharmacological profile.
- GABA A Rs containing al subunits mediate the sedative and amnestic effects of benzodiazepines preferentially, whereas GABA A RS containing a2 and a3 subunits mediate their anxiolytic effects (Rudolph et ah, 1999); Mohler et ah, 2002).
- Partial inverse agonists with low affinity for these receptor subtypes offer the potential advantage of a wider therapeutic concentration range and a lower likelihood of producing negative side effects, such as anxiety or epileptiform discharge.
- a5-subunit mRNA is abundant in pyramidal cells in the hippocampus and deep layers of the neocortex, and a5-containing GABA A Rs are localized at synaptic and extrasynaptic sites in the dendrites (Fritschy and Mohler, 1995; Wainwright et ah, 2000; Serwanski et ah, 2006).
- a5-containing GABA A RS mediate tonic inhibition (Caraiscos et ah, 2004) and lower the excitability of pyramidal cells (Bonin et ah, 2006), so negative allosteric modulators of a5- containing GABA A Rs should promote coherent activity (Hajos et ah, 2004; Towers et ah, 2004). Drugs targeting these receptors are thus an attractive means to selectively alter activity within cortico-mesolimbic circuits without altering activity in other circuits. Indeed, deletion of the a5 gene alters learning in hippocampal-dependent tasks but not hippocampal-independent ones (Collinson et ah, 2002). Interestingly, alpha5 subunits are up-regulated in mice after chronic stress (Matsumoto et ah, 2007), suggesting a role for the alpha5 subunit in the cognitive deficits associated with chronic stress and depression, in particular embodiments.
- SSRIs (Cai et ah, 2013), ketamine (Autry et ah, 2011; Li et ah, 2010), and L-655,708 all enhance excitatory synaptic strength at multiple sites within the cortico- mesolimbic reward circuitry, thereby providing strong support for an association between the restoration of excitatory synaptic strength and the reversal of depressive behavioral phenotypes (Duman, 2014).
- TA-CA1 synapses are not uniquely sensitive to stress or responsive to antidepressants, but they do serve as a convenient archetype of stress-induced changes that are likely occurring at many synapses in the cortico-mesolimbic reward circuitry (Lim et al., 2012; Yuen et al., 2012). The net effect of this weakening is likely to be a dysfunction in processing of rewarding stimuli which may underlie common symptoms of depression, such as anhedonia (Nestler and Carlezon, 2006). Restoration of the strength of these synapses by effective antidepressants should restore normal responses to rewarding stimuli (Belujon and Grace, 2014).
- ketamine Acute administration of ketamine improves mood and reduces depressive symptoms within 1-2 hours in humans and these effects persist for up to two weeks. Similarly, ketamine restores sucrose preference and novelty suppressed feeding behaviors rapidly (24 hrs) in chronically stressed animals (Li et al., 2011). Ketamine's therapeutic effects are induced during the brief period (ca. 1-2 hours) when it is present in the brain at sufficient concentrations to inhibit NMDARs, triggering relief of symptoms that persist for days after it is cleared from the body.
- ketamine may preferentially reduce excitation of GABAergic inhibitory interneurons (Dwyer and Duman, 2013; Farber et al., 1998; Homayoun and Moghaddam, 2007), thereby producing a mild disinhibition of the neuronal population and increased activity in the hippocampus, entorhinal cortex, NAc, and PFC, as observed in rodents (e.g. Kittelberger et al., 2012; Middleton et al., 2008; Hunt et al., 2011) and in humans (Cornwell et al., 2012; Driesen et al., 2013).
- a5-selective benzodiazepine inverse agonists also produce mild disinhibition through their negative allosteric actions, and should therefore also trigger an increased coherence in oscillatory activity, as has been observed following injection of nonselective benzodiazepine inverse agonists (Hajos et al., 2004).
- the ability of both L-655,708 and ketamine to promote activity accounts for their shared antidepressant efficacy because such activity strengthens excitatory synapses via convergence onto common activity-dependent signaling pathways.
- Potential activity-dependent processes include an increase in BDNF signaling, activation of mTOR signaling, and protein synthesis (Autry et al., 2011; Li et al., 2010; 2011).
- An increase in coherent circuit activity is also likely to promote the induction of long-term potentiation (e.g. Huerta and Lisman, 1993). All of these activity-dependent processes have been shown to strengthen excitatory synapses.
- L-655,708 administration triggers a rapid increase in GluAl protein levels in the distal dendrites of CA1 pyramidal cells, coincident with an increase in AMPAR-mediated synaptic excitation.
- chronic, but not acute, administration of SSRIs also promotes GluAl protein levels in this same region (Kallarackal et al, 2013), which is densely innervated with serotonergic terminals.
- SSRIs are reasonably safe and well tolerated, and are not addictive, they are effective in only a subset of patients and only after a delay of weeks-to-months.
- Ketamine exerts a rapid antidepressant action in the majority of patients, but its therapeutic viability is extremely limited to its dissociative and anesthetic properties, as well as its potential for abuse and overdose.
- L-655,708 reversed stress-induced behavioral changes and restored AMPAR-mediated excitatory synaptic strength in two well-validated rodent models of antidepressant efficacy, like SSRIs and ketamine.
- partial inverse agonists of benzodiazepine receptors acting on alpha5-subunit containing GABA A Rs represent a novel, rapidly acting, effective, and clinically viable treatment for human depression.
- GABA A -receptor heterogeneity in the adult rat brain differential regional and cellular distribution of seven major subunits.
- Etomidate targets a5 ⁇ -aminobutyric acid subtype A receptors to regulate synaptic plasticity and memory blockade.
- Ketamine at a dose that disrupts motor behavior and latent inhibition, enhances prefrontal cortex synaptic efficacy and glutamate release in the nucleus accumbens. Neuropsychopharmacol 32: 719-727.
- Alpha 5 subunit-containing GABAA receptors affect the dynamic range of mouse hippocampal kainate- induced gamma frequency oscillations in vitro. J Physiol 559: 721-728.
- Zarate CA Singh JB, Carlson PJ, Bloise NE, Ameli R, Luckenbaugh DA et al (2006).
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